PROJECT SUMMARY/ABSTRACT This K01 proposal seeks to further the career of the Candidate (Dr. Meghan Martz) through a mentored research project and training plan focused on innovative neuroimaging methods, advanced neural network analysis, and a theoretical framework in cognitive neuroscience applied to substance use research. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf), which measures volitional control over targeted brain activity, may provide a novel way to measure the differential timing of the earlier developed reward system in relation to the more gradually maturing cognitive control system that contributes to risk-taking behaviors during adolescence, such as alcohol use. Sex differences in this developmental imbalance, and in substance use outcomes, have also been documented. This K01 proposal intends to extend research on neural function involved in self-control of reward responding by examining if neuromodulation of the reward system and neural networks involved in this system vary by age and sex. Developmental and sex differences in the ability up- and down-regulate brain activity in the nucleus accumbens (NAcc), a key brain region within the reward system, through rtfMRI-nf will be tested at the University of Michigan in adolescents (n=100; 14?16 years old; 50% female) and young adults (n=100; 25?27 years old; 50% female). In the adolescent sample, the interaction between cognitive control and reward responding measured by rtfMRI-nf and neural network profiles will be examined as predictors of alcohol and drug use outcomes assessed over the course of two years. The specific research aims are to: 1) characterize developmental and sex differences in volitional control of the reward system using rtfMRI-nf to regulate NAcc activity; 2) examine developmental and sex differences in neural network profiles associated with reward system regulation using dynamic causal modeling (DCM) to assess effective connectivity with the NAcc during neurofeedback; and 3) investigate the prospective association between reward system modulation and later alcohol and drug use outcomes measured every six months for a two year period (exploratory aim). The following training objectives will ensure that Dr. Martz will successfully achieve these aims and is equipped to become an independent researcher: 1) acquire skills in the design, implementation, and analysis of rtfMRI-nf research; 2) obtain training in neural network analysis and dynamic causal modeling; and 3) gain expertise in cognitive neuroscience applied to substance use research. The training activities and mentorship outlined in the Career Development Plan will ensure the completion of these objectives. Dr. Martz's short-term career goal is to obtain new skills in advanced fMRI methodology and analyses in order to become an independent investigator in substance use research. Her long-term career goal is to develop a comprehensive research program to study neural correlates of self-control associated with alcohol and drug use in youth. The proposed Mentored Research Scientist Development award is an essential first step in fulfilling these career goals.